Differential ability of the dorsal and ventral rat hippocampus to exhibit group I metabotropic glutamate receptor-dependent synaptic and intrinsic plasticity.

Background: The hippocampus is critically involved in learning and memory processes. Although once considered a relatively homogenous structure, it is now clear that the hippocampus can be divided along its longitudinal axis into functionally distinct domains, responsible for the encoding of different types of memory or behaviour. Although differences in extrinsic connectivity are likely to contribute to this functional differentiation, emerging evidence now suggests that cellular and molecular differences at the level of local hippocampal circuits may also play a role.

Forebrain-selective AMPA-receptor antagonism guided by TARP γ-8 as an antiepileptic mechanism.

Pharmacological manipulation of specific neural circuits to optimize therapeutic index is an unrealized goal in neurology and psychiatry. AMPA receptors are important for excitatory synaptic transmission, and their antagonists are antiepileptic. Although efficacious, AMPA-receptor antagonists, including perampanel (Fycompa), the only approved antagonist for epilepsy, induce dizziness and motor impairment.

Group I mGluR Induced LTD of NMDAR-synaptic Transmission at the Schaffer Collateral but not Temperoammonic Input to CA1.

NMDA receptors are composed of multiple subunits and are crucial in the induction of synaptic plasticity and learning and memory. In this study, application of the group I mGlu receptor agonist, DHPG, caused LTD of NMDA-EPSCs (DHPG-LTDNMDA) of the Schaffer collateral, but not of NMDA-EPSCs of the temperoammonic pathway onto CA1 neurons of the hippocampus. DHPGLTDNMDA did not alter the sensitivity of NMDA-EPSC to the GluN2B-antagonist, Ro25-6981, indicating that the postsynaptic NMDA receptor subunit composition remained unchanged following DHPG-LTDNMDA.

In vitro pharmacological and rat pharmacokinetic characterization of LY3020371, a potent and selective mGlu receptor antagonist.

Metabotropic glutamate (mGlu) receptors are of considerable interest owing to their role in modulating glutamate transmission via presynaptic, postsynaptic and glial mechanisms. As part of our ongoing efforts to identify novel ligands for these receptors, we have discovered (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.

Activation of Muscarinic M1 Acetylcholine Receptors Induces Long-Term Potentiation in the Hippocampus.

Muscarinic M1 acetylcholine receptors (M1Rs) are highly expressed in the hippocampus, and their inhibition or ablation disrupts the encoding of spatial memory. It has been hypothesized that the principal mechanism by which M1Rs influence spatial memory is by the regulation of hippocampal synaptic plasticity. Here, we use a combination of recently developed, well characterized, selective M1R agonists and M1R knock-out mice to define the roles of M1Rs in the regulation of hippocampal neuronal and synaptic function.

mGlu1 receptor-induced LTD of NMDA receptor transmission selectively at Schaffer collateral-CA1 synapses mediates metaplasticity.

Hippocampal CA1 pyramidal neurons receive inputs from entorhinal cortex directly via the temporoammonic (TA) pathway and indirectly via the Schaffer collateral (SC) pathway from CA3. NMDARs at synapses of both pathways are critical for the induction of synaptic plasticity, information processing, and learning and memory. We now demonstrate that, in the rat hippocampus, activity-dependent mGlu1 receptor-mediated LTD (mGlu1-LTD) of NMDAR-mediated transmission (EPSC(NMDA)) at the SC-CA1 input prevents subsequent LTP of AMPAR-mediated transmission.

Different NMDA receptor subtypes mediate induction of long-term potentiation and two forms of short-term potentiation at CA1 synapses in rat hippocampus in vitro.

Potentiation at synapses between CA3 and the CA1 pyramidal neurons comprises both transient and sustained phases, commonly referred to as short-term potentiation (STP or transient LTP) and long-term potentiation (LTP), respectively. Here, we utilized four subtype-selective N-methyl-d-aspartate receptor (NMDAR) antagonists to investigate whether the induction of STP and LTP is dependent on the activation of different NMDAR subtypes. We find that the induction of LTP involves the activation of NMDARs containing both the GluN2A and the GluN2B subunits.

Differences in kainate receptor involvement in hippocampal mossy fibre long-term potentiation depending on slice orientation.

Long-term potentiation (LTP) is a well-established experimental model used to investigate the synaptic basis of learning and memory. LTP at mossy fibre - CA3 synapses in the hippocampus is unusual because it is normally N-methyl-d-aspartate (NMDA) receptor-independent. Instead it seems that the trigger for mossy fibre LTP involves kainate receptors (KARs).

Automated multi-slice extracellular and patch-clamp experiments using the WinLTP data acquisition system with automated perfusion control.

WinLTP is a data acquisition program for studying long-term potentiation (LTP) and other aspects of synaptic function. Earlier versions of WinLTP (J. Neurosci.

The methylazoxymethanol acetate (MAM-E17) rat model: molecular and functional effects in the hippocampus.

Administration of the DNA-alkylating agent methylazoxymethanol acetate (MAM) on embryonic day 17 (E17) produces behavioral and anatomical brain abnormalities, which model some aspects of schizophrenia. This has lead to the premise that MAM rats are a neurodevelopmental model for schizophrenia. However, the underlying molecular pathways affected in this model have not been elucidated.

Differential trafficking of AMPA receptors following activation of NMDA receptors and mGluRs.

The removal of AMPA receptors from synapses is a major component of long-term depression (LTD). How this occurs, however, is still only partially understood. To investigate the trafficking of AMPA receptors in real-time we previously tagged the GluA2 subunit of AMPA receptors with ecliptic pHluorin and studied the effects of NMDA receptor activation.

Study of novel selective mGlu2 agonist in the temporo-ammonic input to CA1 neurons reveals reduced mGlu2 receptor expression in a Wistar substrain with an anxiety-like phenotype.

Group II metabotropic receptors (mGluRs) regulate central synaptic transmission by modulating neurotransmitter release. However, the lack of pharmacological tools differentiating between mGlu2 and mGlu3 receptors has hampered identification of the roles of these two receptor subtypes. We have used LY395756 [(1SR,2SR,4RS,5RS,6SR)-2-amino-4-methylbicyclo[3.

LTP in hippocampal neurons is associated with a CaMKII-mediated increase in GluA1 surface expression.

The use of hippocampal dissociated neuronal cultures has enabled the study of molecular changes in endogenous native proteins associated with long-term potentiation. Using immunofluorescence labelling of the active (Thr286-phosphorylated) alpha-Ca(2+) /calmodulin-dependent protein kinase II (CaMKII) we found that CaMKII activity was increased by transient (3 × 1 s) depolarisation in 18- to 21-day-old cultures but not in 9- to 11-day-old cultures. The increase in Thr286 phosphorylation of CaMKII required the activation of NMDA receptors and was greatly attenuated by the CaMKII inhibitor KN-62.

A study of long-term potentiation in transgenic mice over-expressing mutant forms of both amyloid precursor protein and presenilin-1.

Synaptic transmission and long-term potentiation (LTP) in the CA1 region of hippocampal slices have been studied during ageing of a double transgenic mouse strain relevant to early-onset familial Alzheimer's disease (AD). This strain, which over-expresses both the 695 amino acid isoform of human amyloid precursor protein (APP) with K670N and M671L mutations and presenilin 1 with the A246E mutation, has accelerated amyloidosis and plaque formation. There was a decrease in synaptic transmission in both wildtype and transgenic mice between 2 and 9 months of age.

BRAGging about mechanisms of long-term depression.

The mechanisms of long-term depression (LTD) underlie various aspects of normal brain function. Therefore, it is important to understand the signaling that underpins LTD. The study by Scholz et al.

Metabotropic glutamate receptor-mediated long-term depression: molecular mechanisms.

The ability to modify synaptic transmission between neurons is a fundamental process of the nervous system that is involved in development, learning, and disease. Thus, synaptic plasticity is the ability to bidirectionally modify transmission, where long-term potentiation and long-term depression (LTD) represent the best characterized forms of plasticity. In the hippocampus, two main forms of LTD coexist that are mediated by activation of either N-methyl-d-aspartic acid receptors (NMDARs) or metabotropic glutamate receptors (mGluRs).

Disruption of the interaction between myosin VI and SAP97 is associated with a reduction in the number of AMPARs at hippocampal synapses.

Myosin VI is an actin-based motor protein that is enriched at the postsynaptic density and appears to interact with alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate-type glutamate receptors (AMPARs) via synapse associated protein 97 (SAP97). Here, we find that a Flag epitope-tagged dominant negative construct that inhibits the interaction between SAP97 and myosin VI (Flag-myoVI-DN) causes a dramatic reduction in the number of synapses and the surface expression of AMPARs in cultured hippocampal neurons. Furthermore, we find that Flag-myoVI-DN also prevents the rapid delivery of AMPARs to synapses that can be induced by the transient activation of N-methyl-d-aspartate receptors.

Hypothermic responses to infection are inhibited by alpha2-adrenoceptor agonists with possible clinical implications.

Background: alpha(2)-Adrenoceptor agonists are currently used as primary sedative agents in high dependency patients who are at high risk of sepsis. Clinical surveillance of such patients relies in part on their ability to mount appropriate responses to infection, in particular thermal responses. Thermoregulatory responses to infection are well studied in the rat and in this species, and humans, infection can induce febrile, hypothermic, or mixed hypothermic and febrile responses.

GLUK1 receptor antagonists and hippocampal mossy fiber function.

Kainate receptors, one of the three subtypes of ionotropic receptors for the excitatory transmitter l-glutamate, play a variety of functions in the regulation of synaptic activity. Their physiological properties and functional roles have been identified only recently, following the discovery of selective pharmacological tools that allow for isolation of kainate receptor-mediated events. A considerable amount of data indicates that this class of glutamate receptors is located both at the pre- and postsynaptic site, playing a special role in regulating transmission and controlling short- and long-term plasticity.

A systematic investigation of the protein kinases involved in NMDA receptor-dependent LTD: evidence for a role of GSK-3 but not other serine/threonine kinases.

Background: The signalling mechanisms involved in the induction of N-methyl-D-aspartate (NMDA) receptor-dependent long-term depression (LTD) in the hippocampus are poorly understood. Numerous studies have presented evidence both for and against a variety of second messengers systems being involved in LTD induction. Here we provide the first systematic investigation of the involvement of serine/threonine (ser/thr) protein kinases in NMDAR-LTD, using whole-cell recordings from CA1 pyramidal neurons.

ACET is a highly potent and specific kainate receptor antagonist: characterisation and effects on hippocampal mossy fibre function.

Kainate receptors (KARs) are involved in both NMDA receptor-independent long-term potentiation (LTP) and synaptic facilitation at mossy fibre synapses in the CA3 region of the hippocampus. However, the identity of the KAR subtypes involved remains controversial. Here we used a highly potent and selective GluK1 (formerly GluR5) antagonist (ACET) to elucidate roles of GluK1-containing KARs in these synaptic processes.

The use of the hippocampal slice preparation in the study of Alzheimer's disease.

In the present article we show how studying synaptic mechanisms in hippocampal slice preparations provides information that may be useful in, firstly, the understanding of the aetiology of Alzheimer's disease and, secondly, in the development of novel therapies for dementia. We use several examples, drawn from our own work: (i) The identification of the function of AMPA receptors and NMDA receptors in synaptic transmission and synaptic plasticity. (ii) The discovery of mechanisms that can regulate the activation of NMDA receptors.

Co-activation of p38 mitogen-activated protein kinase and protein tyrosine phosphatase underlies metabotropic glutamate receptor-dependent long-term depression.

Long-term potentiation (LTP) and long-term depression (LTD) are forms of synaptic plasticity thought to contribute to learning and memory. Much is known about the mechanisms of NMDA receptor-dependent LTD in the CA1 region of rat hippocampus but there is still considerable uncertainty about the mechanisms of LTD induced by mGluR activation (mGluR-LTD). Furthermore, data on mGluR-LTD derives largely from studies using pharmacologically induced LTD.